1. Field of the Invention
The present invention relates to a method of treatment of diabetic neuropathy, which is a complication of diabetes.
2. Description of the Related Art
Diabetic neuropathy occupies an important place as one of three major complications of diabetes, along with retinopathy and nephropathy, because it develops at relatively earlier stages of diabetes among various other complications of diabetes. It occurs very frequently, ruins patients' quality of life, and leads to distinctively poor prognosis in cases where an autonomic disorder develops as a complication.
Diabetic neuropathy is currently categorized into three groups comprising mononeuropathy, symmetrical peripheral polyneuropathy and autonomic neuropathy (Williams Text Book of Endocrinology, 8th Edition, p. 1301, Harrison's Principles of Internal Medicine, 12th Edition, p. 1754).
Mononeuropathy is a focal or multifocal mononeural disorder which appears as lesions of the cerebral nerve or affects soma and/or extremities. Its major symptom emerges as dyskinesia in many cases. It is known to develop more often in elder patients.
Symmetrical peripheral polyneuropathy is the most frequent form of diabetic neuropathy. It generally makes slow progress, so that patients tend to become aware of the symptoms only after it has reached an advanced stage. The initial symptoms are often a reduced Achilles reflex and a decline or absence of vibratory sensibility. Urtication represented as a smarting feeling and then numbness on both feet follow.
With autonomic neuropathy, patients show representative symptoms for autonomic disorder, such as orthostatic hypotension, cardiac rate alteration, dyshidrosis, atony of esophagus or gastric atony, diabetic diarrhea, impotence and others.
As mechanisms for development of these symptoms, metabolic hypothesis and vascular/ischemic hypothesis have been implied. For the former hypothesis, hyperegasia of polyol metabolic pathway, a pathway where sorbitol and fructose are produced from glucose provided due to hyperglycemia is considered to be the major contributing factor. Another theory involving a reduced content of myoinositol is related to peripheral nerve disorder. In the latter hypothesis, neuro-microvascular occlusion and/or destruction of blood-nerve barrier are thought to be related to the nerve disorders.
For diagnosis and follow-up of diabetic neuropathy a variety of neurologic tests are required. In the first place, Achilles reflex, knee reflex, biceps reflex and triceps reflex are usually examined as deep reflexes. Other than that, tests are performed wherein thermal sensitivity is examined through unmyelinated fibers (C-fibers), cold sensation through small (thinly) myelinated fibers (A.delta.-fibers), heat pain through A.delta.-fibers and C-fibers, and cold pain through C-fibers. Accordingly, for testing sensory nerve functions, vibratory sensibility, pain sensation and thermal sensation (using both warm tests and cold tests) are examined (Clinical Medicine for Diabetic Neuropathy, edited by Masatada Hirata and Norihei Matsuoka, 1992, Gendai-Iryou-sha, p. 95).
Among various neurologic tests, nerve conduction velocity (NCV) examination is the most widely used as a method of objectively evaluating severity of diabetic neuropathy. For motor nerves, two different locations at a nerve are selected to be stimulated with intensities selected to induce the largest peak for each of the corresponding controlling muscles in electromyograms. Then the distance between the two locations is divided by the balance between the obtained latencies in the two electromyograms. The sensory nerve is electrically stimulated in the orthodromic direction at an intensity selected to obtain the largest action potential, and then the distance between the stimulated location and the induced location is divided by the latency.
As methods of treatment of diabetic neuropathy, it has been reported that some trial treatments have been conducted during the 1970s and 1980s based upon the hypothesis that abnormality of metabolic factors is viewed as a cause, Greene D A, De Jesus P V Jr., et al. (Effects of insulin and dietary myoinositol on impaired peripheral motor nerve conduction velocity in acute streptozatocin diabetes; J. Clin. Invest., 1975, 55, 6, 1326-36.) and Yagihashi S., Nishihira M., et al. (Morphometrical analysis of the peripheral nerve lesions in experimental diabetes rats, Tohoku J. Exp. Med., 129, 2, 139-49, 1979). These confirmed that peripheral nerve fibers of model rats for diabetic neuropathy were morphologically impaired and NCV was reduced. In addition to that, they reported that when insulin was administered to the rats, improvements in NCV could been observed, thus finding that control over blood glucose level led to improvements in NCV.
Since then, tests measuring NCV have been always conducted to evaluate the therapeutic efficacy of diabetic neuropathy. Afterward, no adequate results, however, have been practically provided by the treatments for diabetic neuropathy targeting improvements of NCV. In detail, Pietri A, et al. (Changes in nerve conduction velocity after six weeks of glucoregulation with portable insulin infusion pumps.: Diabetes, 29, 8, 668, 1980) and Graf R J, et al. (Glycemic control and nerve conduction abnormalities in non-insulin-dependent diabetic subjects: Ann. Intern. Med., 94, 3, 307, 1981) separately gave drug therapies using insulin to patients with insulin-dependent diabetes and patients with non-insulin-dependent diabetes in 1980 and 1981, respectively, in order to treat diabetic neuropathy. It was consequently reported that motor nerve conduction velocity (MCV) was improved by controlling blood glucose level. It was also reported, however, that only by controlling blood glucose level, improvements in sensory nerve conduction velocity (SCV) could not be observed, and that treatments mainly proposing to control blood glucose level, accordingly, only provided very limited improvements of functions such as thermal sensitivity and vibratory sensibility.
Although Pfeifer M A (Effects of glycemic control and aldose reductase inhibition on nerve conduction velocity: Am. J. Med., 79, 5A, 18-23, 1985) and Yoshio Goto, et al. (Clinical research for diabetic neuropathy using epalrestat (ONO-2235)--Inter-group double-blind placebo (including a trace amount of a curative medicine)-controlled trial: Igaku-no-Ayumi, 152, 6, 405, 1990) tested treatments using aldose reductase inhibitors (ARIs) based upon a hypothesis of abnormality in polyol metabolic pathway as one of the candidates of the cause of the disease in 1985 and 1990, respectively, the effects of aldose reductase inhibitors (ARIs) on improving motor nerve conduction velocity (MCV) and sensory nerve conduction velocity (SCV) remained low.
Accordingly, current methods of treatment for diabetic neuropathy, dietary therapy and administration of insulin, both mainly proposing to control blood glucose level, administration of aldose reductase inhibitors and aminoguanidine, both mainly proposing to improve abnormal glucose metabolism, administration of troglitazone, and administration of agents for limb ischemia mainly proposing to improve blood flow, have been conducted.
In any treatments, improvement of nerve conduction velocity was not always sufficient when a single drug was used, and methods of treatment by combined use of different therapeutic agents which have different functions have yet to be established. Accordingly, combined drug therapies for diabetic neuropathy, aiming at recovering once reduced nerve conduction velocity, have not yet been confirmed.
It has been reported that therapeutic efficacy obtained by single use of an anti-diabetic agent has achieved only limited improvements, i.e., applying 12-week treatment using an aldose reductase inhibitor alone (for 86 subjects), MCV (median motor nerve conduction velocity) and SCV (median sensory nerve conduction velocity) achieved improvement by only 2 m/sec and 3.2 m/sec, respectively. (Clinical research on diabetic neuropathy using epalrestat (ONO-2235)--Double-blind placebo (including a trace amount of a curative medicine)-controlled trial): Igaku-no-Ayumi, 152, 6, 405, 1990). In addition, when treatments with single use of an oral hypoglycemic agent (for 51 subjects) or an insulin (for 10 subjects) had been continued separately for 5 through 10 years, both nerve conduction velocities were rather reduced, i.e. MCV (median motor nerve conduction velocity) and SCV (median sensory nerve conduction velocity) were reduced by 2.9 m/sec and 0.6 m/sec, respectively (Juhani Partanen et al., Natural history of peripheral neuropathy in patients with non-insulin-dependent diabetes mellitus: N. Eng. J. Med., 333, 2, 89-94, 1995). Accordingly, it has been found that using methods of treatment with an anti-diabetic agent alone, nerve conduction velocities were only improved 3.2 m/sec at the best. Even in some cases these velocities rather were reduced as the illness proceeded.
It has been verified through animal experiments using beraprost, a prostaglandin-12 derivative, that beraprost has therapeutic efficacy on diabetic neuropathy. (Publication of unexamined application for Japanese Patent: Serial Number 1990-262519). No reports, however, have been published on combined effects of beraprost with an anti-diabetic agent on diabetic neuropathy aiming at functional improvements of sensory nerve and motor nerve.
As described hereinbefore, in the treatments of diabetic neuropathy aiming at recovering once-reduced nerve conduction velocity, any of the conventional anti-diabetic agents with its single use even shows some effects, but the degrees of which are not evaluated as clinical satisfaction. Moreover, no combined therapies using two curative agents with different functions have yet been achieved.